e116
LETTERS TO THE EDITORS
Successful use of recombinant factor VIIa in a patient with acquired Glanzmann thrombasthenia M . T U F F I G O , * E . L A Z A R O , † ‡ § C . J A M E S , * ‡ § C . S U B T I L , ¶ J . - F . V I A L L A R D † ‡ § and M . F I O R E * ‡ § *Laboratoire d’Hematologie; †Service de Medecine Interne et Maladies Infectieuses, CHU de Bordeaux, Pessac; ‡Universite de Bordeaux, Bordeaux; §INSERM U1034, Adaptation cardiovasculaire a l’ischemie; and ¶Service de gastro-enterologie CHU de Bordeaux, Pessac, France
Immune thrombocytopenic purpura (ITP) is caused by circulating antibodies that react with target antigens on the platelet membrane [1]. In very rare cases, ITP may be associated with acquired Glanzmann thrombasthenia (GT), a severe bleeding disorder [2,3]. While congenital GT is caused by inherited mutations in the genes encoding aIIb or b3 subunits [4], acquired GT results from naturally occurring auto-antibodies directed against the aIIbb3 complex, inhibiting its function. Patients classically present with thrombocytopenia and defective platelet aggregation in response to all physiological stimuli. Occasionally, patients with ITP may require an immediate improvement of the haemostatic capacity due to serious active bleeding or urgent need for invasive procedures. To date, prompt haemostatic management still relies on extensive platelet transfusions. However, in ITP patient with acquired GT, naturally occurring auto-antibodies directed against the aIIbb3 integrin can cause the removal of or render ineffective transfused donor platelets, a crucial problem for the management of these patients. In GT, recombinant FVIIa (Novoseven, Novo Nordisk A/S, Bagsvaerd, Denmark) was approved in France in 2004 but only for treatment of congenital forms with antiplatelet immunization and a history of refractoriness to platelet transfusion [5,6]. Despite previous reports of patients with acquired GT, rFVIIa efficacy has not been well established in this setting. Here, we report the case of an ITP patient with acquired GT who needed emergency invasive procedures that were successfully managed with the use of rFVIIa associated to tranexamic acid. The patient is a 50-year-old man with severe chronic ITP and Crohn’s disease. After unsuccessful splenectomy, romiplostim (Nplate, Amgen, Mississauga, Canada) was initiated and rapidly increased his platelet count. Three months later, in spite of subnormal platelet counts, he suffered from repeated epiCorrespondence: Marie Tuffigo, Laboratoire d’hematologie, H^ opital Cardiologique, 33604 Pessac, France. Tel.: +33557656478; fax: +33557656845; e-mail: [email protected] Accepted after revision 18 October 2014 DOI: 10.1111/hae.12589 Haemophilia (2015), 21, e70--e121
sodes of severe gastrointestinal (GI) bleedings leading to profound anaemia. He was then referred to our centre where a battery of tests was performed on several occasions (signed informed consent was obtained). His initial laboratory values showed the following results: haemoglobin 13.2 g dL1, white cell count 6,000/mm3 and platelets 120,000/mm3. Prothrombin time, partial thromboplastin time and fibrinogen activity were normal. Platelet function analyser (PFA-100) values were greater than 300 s for collagen/ADP (normal < 120 s) and collagen/EPI (normal < 170 s). An acquired von Willebrand disease was excluded with normal VWF:Ag and VWF:RCo. Platelet aggregation studies showed no or much reduced aggregation using ADP (10 lM), arachidonic acid (1 mM), collagen (2 lg mL1) and TRAP (50 lM) agonists (Fig. 1a). In contrast, agglutination with high dose (1.2 mg mL1) of ristocetin was normal. Flow cytometry showed a decreased expression of aIIbb3 when using P2, an antibody which reacts with the aIIb chain of the complex. Moreover, upon stimulation with TRAP, no binding of PAC-1, an activation-dependent antibody which recognizes the ligand-binding site in aIIbb3, was detected by flow cytometry (Fig. 1b). The presence of a reactive antibody against aIIbb3 was also identified (PakAuto, GTI Diagnostics, Waukesha, WI, USA) and a platelet aggregation mixing study demonstrated inhibition of normal donor platelets with the patient’s plasma in presence of TRAP 25 lM (Fig. 1c). Based on these results, acquired GT was diagnosed and an immunosuppressive therapy was started with azathioprine. Two weeks later, he presented to the emergency department with severe anaemia due to a new episode of GI bleeding. Blood results on admission revealed a haemoglobin level of 7.3 g dL1, and platelets of 108,000/mm3. Platelet function defects were still present showing that azathioprine was not efficient. The oesophagogastroduodenoscopy performed was normal and the colonoscopy revealed an active bleeding before the caecum. After administration of one apheresis platelet concentrate, platelets remained at 100,000/mm3; and despite additional platelet concentrates, platelet recovery did not occur. Angiography of the superior mesenteric artery was also performed, leading to the fourth jejunal branch artery embolization. Clinical © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS (a) TRAP
(b) AA
Time (s) ADP
MFI
Collagen
ristocetin
Transmission (%)
(c) Time (s) Control + Patient plasma
Control + Control plasma
Transmission (%)
success was achieved and the patient was discharged 10 days later. Despite embolization and medical therapy, GI bleeding recurred a few days later. Taking into account the severe platelet defect and transfusion refractoriness, haemostatic cover by rFVIIa was planned. A colonoscopy was performed with rFVIIa given 30 min prior to endoscopic examination at 90 lg kg1, and repeated every 3 h for three doses until haemostasis was complete. An ulcerated polyp on the right side of the colon was resected by mucosectomy. Tranexamic acid (50 mg kg1 per day) was also initiated and continued for 48 h. To evaluate side effect of rFVIIa, daily physical examination and laboratory investigations were performed, showing no signs of complications. During follow-up, the patient presented severe abdominal pains and obstructive jaundice. Abdominal ultrasound confirmed the diagnosis of acute cholangitis and the endoscopic retrograde cholangiopancreatography showed the presence of gallstones in the common bile duct. Biliary sphincterotomy during the procedure facilitated stones retrieval. Bleeding prophylaxis also consisted of rFVIIa in combination with antifibrinolytic tranexamic acid on the same regimen as above. He became apyretic with regression of jaundice and there was no sign of bleeding. Classically, in acquired GT, patients should undergo auto-antibodies eradication to restore normal haemostasis. However, immunosuppressive therapy does not provide an optimal response in emergency situations, as platelet functions do not normalize until after sev-
References 1 Andre JM, Galambrun C, Trzeciak MC et al. Acquired Glanzmann’s thrombasthenia associated with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2005; 27: 554–7.
© 2014 John Wiley & Sons Ltd
Acquired GT
NS
P2
MFI
Fig. 1. (a) Aggregation responses (% light transmission) of the patient’s platelets to collagen (2 lg mL1), ADP (10 lM), arachidonic acid (1 mM), TRAP (50 lM) and ristocetin (1.2 mg mL1); (b) flow cytometric analysis of the aIIbb3 complex at platelet surface using monoclonal antibodies (P2/CD41 and PAC-1), NS indicates not stimulated, TRAP indicates samples activated by TRAP; (c) aggregation responses (% light transmission) of control platelet-rich plasma to 25 lM of TRAP evaluated after mixing with patient or control plasma.
Control 80 70 60 50 40 30 20 10 0
e117
9 8 7 6 5 4 3 2 1 0
TRAP
NS
PAC-1
eral weeks of treatment. rFVIIa represents a rational management approach to bleeding complications resulting from platelet disorders. At high concentrations, rFVIIa binds directly to activated platelets to initiate thrombin formation [7]. Data assessing the efficacy and safety of rFVIIa in acquired GT patients undergoing invasive procedures are lacking. The heterogeneity of rFVIIa treatment regimens (doses, duration and associated treatments) is an open issue. Finally, as it is classically recommended in congenital form of GT, the patient received 90 lg kg1 preoperatively, and then twice the same dose every 3 h. No significant blood loss occurred and nor was red cell or platelet transfusion required throughout postoperative periods. Therefore, it appears that this agent could be effective in the treatment of ITP patients with acquired GT, but caution should be exercised relative to the risk of thrombosis events during and following treatment. Anecdotes of the use of rFVIIa therapy in acquired GT remain instructive and may be useful. However, this approach should be studied further and a larger collection of clinical data may be helpful to translate the good efficacy–safety ratio of rFVIIa in this clinical setting. Finally, the potential adverse effect in this treatment still needs a lot of work to verify.
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
2 Bloor AJ, Smith GA, Jaswon M, Parker NE, Ouwehand WH, Liesner R. Acquired thrombasthenia due to GPIIbIIIa platelet autoantibodies in a 4-yrold child. Eur J Haematol 2006; 76: 89–90.
3 Morath C, Hoffmann T, Kirchhoff EM et al. Acquired Glanzmann’s thrombasthenia variant and immune thrombocytopenia in a renal transplant recipient receiving tacrolimus. Thromb Haemost 2005; 94: 879–80.
Haemophilia (2015), 21, e70--e121
e118
LETTERS TO THE EDITORS
4 Fiore M, Nurden AT, Nurden P, Seligsohn U. Clinical utility gene card for: Glanzmann thrombasthenia. Eur J Hum Genet 2012; 20: 1102. 5 Fiore M, Firah N, Pillois X, Nurden P, Heilig R, Nurden AT. Natural history of platelet
antibody formation against alphaIIbbeta3 in a French cohort of Glanzmann thrombasthenia patients. Haemophilia 2012; 18: e201–9. 6 Seligsohn U. Treatment of inherited platelet disorders. Haemophilia 2012; 18(Suppl. 4): 161–5.
7 Hedner U, Erhardtsen E. Potential role of recombinant factor VIIa as a hemostatic agent. Clin Adv Hematol Oncol 2003; 1: 112–9.
The use of recombinant factor XIII in a major bleeding episode of a patient with congenital factor XIII deficiency – the first experience O K S Z AL L AS I , * A . K E R EN Y I , † E. KATONA,‡ Z. BERECZKY,‡ L. MUSZBEK,‡ Z. BODA* A . AR SCHLAMMADINGER* and A. *Thrombosis and Haemostasis Centre, Institute of Medicine, University of Debrecen; †Institute of Laboratory Medicine University of Debrecen; and ‡Clinical Research Centre, University of Debrecen, Debrecen, Hungary
Congenital factor XIII (FXIII) deficiency is a rare, autosomal-recessive bleeding diathesis that can be associated with impaired wound healing and recurrent miscarriages. Delayed umbilical cord bleeding is a typical early presentation. Intracranial haemorrhage develops far more frequently than in any other inherited bleeding disorder. Therefore, life-long prophylactic factor supplementation is mandatory if FXIII activity is below 1%. Subcutaneous, mucosal, intramuscular or joint bleeding and postoperative haemorrhage can also occur [1]. Previously, plasma-derived sources of FXIII were available for preventive and on-demand therapy. A novel option for FXIII replacement is a recombinant FXIII (rFXIII) concentrate (catridecacog, NovoThirteenâ, Novo Nordisk, Bagsvaerd, Denmark) that contains the A subunit (FXIII-A) from the tetramer of plasma FXIII-A2B2. Recombinant FXIII-A2 (rFXIII-A2) combines with endogenous B subunit (FXIII-B) to form stable FXIII-rA2B2 reaching a half-life of 6–12 days [2,3]. Currently rFXIII is licensed for monthly prophylaxis in a dose of 35 IU kg1 in severe congenital FXIII-A subunit deficiency [www. ema.europa.eu, www.fda.gov]. The efficacy and safety of rFXIII have not been tested in acute bleeding. However, pharmacokinetic profile of rFXIII [3] supports the hypothesis that it is also suitable for on-demand therapy [1]. This letter reports the effective use of rFXIII for the treatment of a major bleeding in a patient with severe congenital FXIII-A deficiency. Correspondence: Agota Schlammadinger, Nagyerdei krt. 98., H-4012 Debrecen, Hungary. Tel./fax: +36-52-255-152; e-mail: [email protected] Accepted after revision 26 October 2014 DOI: 10.1111/hae.12591 Haemophilia (2015), 21, e70--e121
A 19-year-old man exhibiting severe bleeding phenotype without clear diagnosis was referred to our haemostasis laboratory. In infancy he was hospitalized due to prolonged umbilical cord haemorrhage; later he suffered a subdural haematoma, recurrent subcutaneous bleeding, intramuscular haematomas and haemarthroses. He has had up to five major bleeding events per year, which developed spontaneously or after minor trauma. There was no family history of bleeding diathesis. Despite extensive evaluation for coagulation defect, no definitive diagnosis could be confirmed. Haemorrhages were treated successfully with fresh frozen plasma in a dose of 4.2–13.3 mL kg1. In our centre, re-evaluation of the case revealed severe congenital type I FXIII-A deficiency (Table 1) considering the current classification of the disease [4]. Consequently life-long preventive FXIII replacement was recommended for the patient. Due to his young age and negative viral status (human immunodeficiency, hepatitis B and C viruses) rFXIII concentrate was preferred for factor supplementation. A week before the appointment for the first rFXIII infusion the patient was admitted to our clinic due to the swelling and pain of the right thigh that caused loss of mobility. The symptoms began 3 days before hospitalization after having performed hard physical activity. No traumatic event occurred. Physical examination revealed a huge tough resistance in the upper third part of the right thigh that led to eight cm surplus in the circumference compared with the left thigh (62 vs. 54 cm). Computed tomography excluded the presence of retroperitoneal or pelvic haemorrhages, but described a huge intramuscular haematoma in the proximal and mediodorsal region of the right thigh with diameters of 7.7, 8.3 and 19.0 cm. Intramuscular haematoma was considered to be a major bleeding event © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
Successful use of recombinant factor VIIa in a patient with acquired Glanzmann thrombasthenia M . T U F F I G O , * E . L A Z A R O , † ‡ § C . J A M E S , * ‡ § C . S U B T I L , ¶ J . - F . V I A L L A R D † ‡ § and M . F I O R E * ‡ § *Laboratoire d’Hematologie; †Service de Medecine Interne et Maladies Infectieuses, CHU de Bordeaux, Pessac; ‡Universite de Bordeaux, Bordeaux; §INSERM U1034, Adaptation cardiovasculaire a l’ischemie; and ¶Service de gastro-enterologie CHU de Bordeaux, Pessac, France
Immune thrombocytopenic purpura (ITP) is caused by circulating antibodies that react with target antigens on the platelet membrane [1]. In very rare cases, ITP may be associated with acquired Glanzmann thrombasthenia (GT), a severe bleeding disorder [2,3]. While congenital GT is caused by inherited mutations in the genes encoding aIIb or b3 subunits [4], acquired GT results from naturally occurring auto-antibodies directed against the aIIbb3 complex, inhibiting its function. Patients classically present with thrombocytopenia and defective platelet aggregation in response to all physiological stimuli. Occasionally, patients with ITP may require an immediate improvement of the haemostatic capacity due to serious active bleeding or urgent need for invasive procedures. To date, prompt haemostatic management still relies on extensive platelet transfusions. However, in ITP patient with acquired GT, naturally occurring auto-antibodies directed against the aIIbb3 integrin can cause the removal of or render ineffective transfused donor platelets, a crucial problem for the management of these patients. In GT, recombinant FVIIa (Novoseven, Novo Nordisk A/S, Bagsvaerd, Denmark) was approved in France in 2004 but only for treatment of congenital forms with antiplatelet immunization and a history of refractoriness to platelet transfusion [5,6]. Despite previous reports of patients with acquired GT, rFVIIa efficacy has not been well established in this setting. Here, we report the case of an ITP patient with acquired GT who needed emergency invasive procedures that were successfully managed with the use of rFVIIa associated to tranexamic acid. The patient is a 50-year-old man with severe chronic ITP and Crohn’s disease. After unsuccessful splenectomy, romiplostim (Nplate, Amgen, Mississauga, Canada) was initiated and rapidly increased his platelet count. Three months later, in spite of subnormal platelet counts, he suffered from repeated epiCorrespondence: Marie Tuffigo, Laboratoire d’hematologie, H^ opital Cardiologique, 33604 Pessac, France. Tel.: +33557656478; fax: +33557656845; e-mail: [email protected] Accepted after revision 18 October 2014 DOI: 10.1111/hae.12589 Haemophilia (2015), 21, e70--e121
sodes of severe gastrointestinal (GI) bleedings leading to profound anaemia. He was then referred to our centre where a battery of tests was performed on several occasions (signed informed consent was obtained). His initial laboratory values showed the following results: haemoglobin 13.2 g dL1, white cell count 6,000/mm3 and platelets 120,000/mm3. Prothrombin time, partial thromboplastin time and fibrinogen activity were normal. Platelet function analyser (PFA-100) values were greater than 300 s for collagen/ADP (normal < 120 s) and collagen/EPI (normal < 170 s). An acquired von Willebrand disease was excluded with normal VWF:Ag and VWF:RCo. Platelet aggregation studies showed no or much reduced aggregation using ADP (10 lM), arachidonic acid (1 mM), collagen (2 lg mL1) and TRAP (50 lM) agonists (Fig. 1a). In contrast, agglutination with high dose (1.2 mg mL1) of ristocetin was normal. Flow cytometry showed a decreased expression of aIIbb3 when using P2, an antibody which reacts with the aIIb chain of the complex. Moreover, upon stimulation with TRAP, no binding of PAC-1, an activation-dependent antibody which recognizes the ligand-binding site in aIIbb3, was detected by flow cytometry (Fig. 1b). The presence of a reactive antibody against aIIbb3 was also identified (PakAuto, GTI Diagnostics, Waukesha, WI, USA) and a platelet aggregation mixing study demonstrated inhibition of normal donor platelets with the patient’s plasma in presence of TRAP 25 lM (Fig. 1c). Based on these results, acquired GT was diagnosed and an immunosuppressive therapy was started with azathioprine. Two weeks later, he presented to the emergency department with severe anaemia due to a new episode of GI bleeding. Blood results on admission revealed a haemoglobin level of 7.3 g dL1, and platelets of 108,000/mm3. Platelet function defects were still present showing that azathioprine was not efficient. The oesophagogastroduodenoscopy performed was normal and the colonoscopy revealed an active bleeding before the caecum. After administration of one apheresis platelet concentrate, platelets remained at 100,000/mm3; and despite additional platelet concentrates, platelet recovery did not occur. Angiography of the superior mesenteric artery was also performed, leading to the fourth jejunal branch artery embolization. Clinical © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS (a) TRAP
(b) AA
Time (s) ADP
MFI
Collagen
ristocetin
Transmission (%)
(c) Time (s) Control + Patient plasma
Control + Control plasma
Transmission (%)
success was achieved and the patient was discharged 10 days later. Despite embolization and medical therapy, GI bleeding recurred a few days later. Taking into account the severe platelet defect and transfusion refractoriness, haemostatic cover by rFVIIa was planned. A colonoscopy was performed with rFVIIa given 30 min prior to endoscopic examination at 90 lg kg1, and repeated every 3 h for three doses until haemostasis was complete. An ulcerated polyp on the right side of the colon was resected by mucosectomy. Tranexamic acid (50 mg kg1 per day) was also initiated and continued for 48 h. To evaluate side effect of rFVIIa, daily physical examination and laboratory investigations were performed, showing no signs of complications. During follow-up, the patient presented severe abdominal pains and obstructive jaundice. Abdominal ultrasound confirmed the diagnosis of acute cholangitis and the endoscopic retrograde cholangiopancreatography showed the presence of gallstones in the common bile duct. Biliary sphincterotomy during the procedure facilitated stones retrieval. Bleeding prophylaxis also consisted of rFVIIa in combination with antifibrinolytic tranexamic acid on the same regimen as above. He became apyretic with regression of jaundice and there was no sign of bleeding. Classically, in acquired GT, patients should undergo auto-antibodies eradication to restore normal haemostasis. However, immunosuppressive therapy does not provide an optimal response in emergency situations, as platelet functions do not normalize until after sev-
References 1 Andre JM, Galambrun C, Trzeciak MC et al. Acquired Glanzmann’s thrombasthenia associated with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2005; 27: 554–7.
© 2014 John Wiley & Sons Ltd
Acquired GT
NS
P2
MFI
Fig. 1. (a) Aggregation responses (% light transmission) of the patient’s platelets to collagen (2 lg mL1), ADP (10 lM), arachidonic acid (1 mM), TRAP (50 lM) and ristocetin (1.2 mg mL1); (b) flow cytometric analysis of the aIIbb3 complex at platelet surface using monoclonal antibodies (P2/CD41 and PAC-1), NS indicates not stimulated, TRAP indicates samples activated by TRAP; (c) aggregation responses (% light transmission) of control platelet-rich plasma to 25 lM of TRAP evaluated after mixing with patient or control plasma.
Control 80 70 60 50 40 30 20 10 0
e117
9 8 7 6 5 4 3 2 1 0
TRAP
NS
PAC-1
eral weeks of treatment. rFVIIa represents a rational management approach to bleeding complications resulting from platelet disorders. At high concentrations, rFVIIa binds directly to activated platelets to initiate thrombin formation [7]. Data assessing the efficacy and safety of rFVIIa in acquired GT patients undergoing invasive procedures are lacking. The heterogeneity of rFVIIa treatment regimens (doses, duration and associated treatments) is an open issue. Finally, as it is classically recommended in congenital form of GT, the patient received 90 lg kg1 preoperatively, and then twice the same dose every 3 h. No significant blood loss occurred and nor was red cell or platelet transfusion required throughout postoperative periods. Therefore, it appears that this agent could be effective in the treatment of ITP patients with acquired GT, but caution should be exercised relative to the risk of thrombosis events during and following treatment. Anecdotes of the use of rFVIIa therapy in acquired GT remain instructive and may be useful. However, this approach should be studied further and a larger collection of clinical data may be helpful to translate the good efficacy–safety ratio of rFVIIa in this clinical setting. Finally, the potential adverse effect in this treatment still needs a lot of work to verify.
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
2 Bloor AJ, Smith GA, Jaswon M, Parker NE, Ouwehand WH, Liesner R. Acquired thrombasthenia due to GPIIbIIIa platelet autoantibodies in a 4-yrold child. Eur J Haematol 2006; 76: 89–90.
3 Morath C, Hoffmann T, Kirchhoff EM et al. Acquired Glanzmann’s thrombasthenia variant and immune thrombocytopenia in a renal transplant recipient receiving tacrolimus. Thromb Haemost 2005; 94: 879–80.
Haemophilia (2015), 21, e70--e121
e118
LETTERS TO THE EDITORS
4 Fiore M, Nurden AT, Nurden P, Seligsohn U. Clinical utility gene card for: Glanzmann thrombasthenia. Eur J Hum Genet 2012; 20: 1102. 5 Fiore M, Firah N, Pillois X, Nurden P, Heilig R, Nurden AT. Natural history of platelet
antibody formation against alphaIIbbeta3 in a French cohort of Glanzmann thrombasthenia patients. Haemophilia 2012; 18: e201–9. 6 Seligsohn U. Treatment of inherited platelet disorders. Haemophilia 2012; 18(Suppl. 4): 161–5.
7 Hedner U, Erhardtsen E. Potential role of recombinant factor VIIa as a hemostatic agent. Clin Adv Hematol Oncol 2003; 1: 112–9.
The use of recombinant factor XIII in a major bleeding episode of a patient with congenital factor XIII deficiency – the first experience O K S Z AL L AS I , * A . K E R EN Y I , † E. KATONA,‡ Z. BERECZKY,‡ L. MUSZBEK,‡ Z. BODA* A . AR SCHLAMMADINGER* and A. *Thrombosis and Haemostasis Centre, Institute of Medicine, University of Debrecen; †Institute of Laboratory Medicine University of Debrecen; and ‡Clinical Research Centre, University of Debrecen, Debrecen, Hungary
Congenital factor XIII (FXIII) deficiency is a rare, autosomal-recessive bleeding diathesis that can be associated with impaired wound healing and recurrent miscarriages. Delayed umbilical cord bleeding is a typical early presentation. Intracranial haemorrhage develops far more frequently than in any other inherited bleeding disorder. Therefore, life-long prophylactic factor supplementation is mandatory if FXIII activity is below 1%. Subcutaneous, mucosal, intramuscular or joint bleeding and postoperative haemorrhage can also occur [1]. Previously, plasma-derived sources of FXIII were available for preventive and on-demand therapy. A novel option for FXIII replacement is a recombinant FXIII (rFXIII) concentrate (catridecacog, NovoThirteenâ, Novo Nordisk, Bagsvaerd, Denmark) that contains the A subunit (FXIII-A) from the tetramer of plasma FXIII-A2B2. Recombinant FXIII-A2 (rFXIII-A2) combines with endogenous B subunit (FXIII-B) to form stable FXIII-rA2B2 reaching a half-life of 6–12 days [2,3]. Currently rFXIII is licensed for monthly prophylaxis in a dose of 35 IU kg1 in severe congenital FXIII-A subunit deficiency [www. ema.europa.eu, www.fda.gov]. The efficacy and safety of rFXIII have not been tested in acute bleeding. However, pharmacokinetic profile of rFXIII [3] supports the hypothesis that it is also suitable for on-demand therapy [1]. This letter reports the effective use of rFXIII for the treatment of a major bleeding in a patient with severe congenital FXIII-A deficiency. Correspondence: Agota Schlammadinger, Nagyerdei krt. 98., H-4012 Debrecen, Hungary. Tel./fax: +36-52-255-152; e-mail: [email protected] Accepted after revision 26 October 2014 DOI: 10.1111/hae.12591 Haemophilia (2015), 21, e70--e121
A 19-year-old man exhibiting severe bleeding phenotype without clear diagnosis was referred to our haemostasis laboratory. In infancy he was hospitalized due to prolonged umbilical cord haemorrhage; later he suffered a subdural haematoma, recurrent subcutaneous bleeding, intramuscular haematomas and haemarthroses. He has had up to five major bleeding events per year, which developed spontaneously or after minor trauma. There was no family history of bleeding diathesis. Despite extensive evaluation for coagulation defect, no definitive diagnosis could be confirmed. Haemorrhages were treated successfully with fresh frozen plasma in a dose of 4.2–13.3 mL kg1. In our centre, re-evaluation of the case revealed severe congenital type I FXIII-A deficiency (Table 1) considering the current classification of the disease [4]. Consequently life-long preventive FXIII replacement was recommended for the patient. Due to his young age and negative viral status (human immunodeficiency, hepatitis B and C viruses) rFXIII concentrate was preferred for factor supplementation. A week before the appointment for the first rFXIII infusion the patient was admitted to our clinic due to the swelling and pain of the right thigh that caused loss of mobility. The symptoms began 3 days before hospitalization after having performed hard physical activity. No traumatic event occurred. Physical examination revealed a huge tough resistance in the upper third part of the right thigh that led to eight cm surplus in the circumference compared with the left thigh (62 vs. 54 cm). Computed tomography excluded the presence of retroperitoneal or pelvic haemorrhages, but described a huge intramuscular haematoma in the proximal and mediodorsal region of the right thigh with diameters of 7.7, 8.3 and 19.0 cm. Intramuscular haematoma was considered to be a major bleeding event © 2014 John Wiley & Sons Ltd
